Preparation of Functionalized Aryl, Heteroaryl, and Benzylic Potassium Organometallics Using Potassium Diisopropylamide in Continuous Flow

Article abstract of DOI:10.1002/anie.202003392

We report the preparation of lithium-salt-free KDA (potassium diisopropylamide; 0.6 m in hexane) complexed with TMEDA (N,N,N′,N′-tetramethylethylenediamine) and its use for the flow-metalation of (hetero)arenes between ?78 °C and 25 °C with reaction times between 0.2 s and 24 s and a combined flow rate of 10 mL min^?1 using a commercial flow setup. The resulting potassium organometallics react instantaneously with various electrophiles, such as ketones, aldehydes, alkyl and allylic halides, disulfides, Weinreb amides, and Me₃SiCl, affording functionalized (hetero)arenes in high yields. This flow procedure is successfully extended to the lateral metalation of methyl-substituted arenes and heteroaromatics, resulting in the formation of various benzylic potassium organometallics. A metalation scale-up was possible without further optimization.

Full text of DOI:10.1002/anie.202003392

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Accepted Article
Title: Preparation of Functionalized Aryl, Heteroaryl and Benzylic
Potassium Organometallics using Potassium Diisopropylamide in
Continuous Flow
Authors: Johannes H. Harenberg, Niels Weidmann, and Paul Knochel
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003392
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10.1002/anie.202003392
Angewandte Chemie International Edition
COMMUNICATION
Preparation of Functionalized Aryl, Heteroaryl and Benzylic
Potassium Organometallics using Potassium Diisopropylamide in
Continuous Flow
Johannes H. Harenberg,#,[a] Niels Weidmann,#,[a] and Paul Knochel*[a]
Dedicated to Prof. Dr. Rolf Huisgen for his 100th birthday
[a]
J. H. Harenberg, N. Weidmann,
Prof. Dr. P. Knochel,
Department Chemie
Ludwig-Maximilians-Universität München
Butenandtstrasse 5-13, Haus F, 81377 München (Germany)
paul.knochel@cup.uni-muenchen.de
These authors contributed equally.
#
Supporting information for this article is given via a link at the end of the document.
Abstract: We report the preparation of lithium salt free KDA
(potassium diisopropylamide; 0.6 M in hexane) complexed with
TMEDA (N,N,N',N'-tetramethylethylenediamine) and its use for the
flow-metalation of (hetero)arenes between -78 °C and 25 °C with
reaction times between 0.2 s and 24 s and a combined flow rate of 10
mL/min using a commercial flow set-up. The resulting potassium
organometallics react instantaneously with various electrophiles, such
as ketones, aldehydes, alkyl and allylic halides, disulfides, Weinreb
amides and Me3SiCl, affording functionalized (hetero)arenes in high
yields. This flow procedure is successfully extended to the lateral
metalation of methyl-substituted arenes and heteroaromatics
resulting in the formation of various benzylic potassium
organometallics. A metalation scale-up was possible without further
optimization.
entries 1-6). The resulting KDA/TMEDA solution was titrated with
a standardized solution of 0.40 M n-butanol in hexane. In most
cases, an excess of potassium (ca. 3 equiv) was used and the
KDA/TMEDA yield was calculated based on diisopropylamine
(1.0 equiv). We have varied the equivalents of TMEDA and
isoprene (entries 1-4) and found that 1.0 equivalent of TMEDA
and 0.5 equivalent of isoprene resulted in the best yield after 6 h
reaction time (entry 4).[6a] Longer stirring did not improve the yield.
Such KDA/TMEDA solutions were stable for at least one week at
25 °C. Similar yields were obtained using cyclohexane instead of
hexane (entry 5). A quantitative yield was reached by setting
potassium as limiting reagent (1.0 equiv) and adding an excess of
diisopropylamine (DIPA, 3.0 equiv), TMEDA (3.0 equiv) and
isoprene (1.5 equiv; entry 6). Attempts to extend this preparation
to 2,2,6,6-tetramethylpiperidine (TMPH) or Cy2NH led to
significantly lower yields (entries 7-8). For subsequent
experiments performed in continuous flow, we have used the
KDA/TMEDA preparation conditions described in entry 4.
From all the alkali metals, lithium has by far received the most
applications in organic synthesis.[1] However, the use of sodium
and potassium organometallic intermediates has been explored
since more than a century[2] and presents several specific
advantages such as enhanced reactivity, low prices and
moderate toxicity of these alkali organometallics as well as
opportunities for new metalation selectivities.[3] Recently, we have
reported that the use of continuous flow techniques[4]
considerably facilitates the use of sodium bases such as NaDA
(sodium diisopropylamide) for the selective sodiation of aromatics
and heterocycles.[5] Herein, we wish to report a new metalation
procedure allowing both to perform arene and heteroarene
metalations as well as lateral metalations using potassium
Table 1. Optimization of the preparation of potassium amide bases using solid
potassium, secondary amides, TMEDA and isoprene in hexane.
R2NH
1.0 equiv
TMEDA
X equiv
Isoprene
X equiv
Molarity
(K-base)
Yield
(%)
Entry
t [h]
1
2
3
4
DIPA
DIPA
DIPA
DIPA
2.7
1.0
2.7
1.0
0.5
1.0
1.0
0.5
6
6
6
6
0.33
0.40
0.50
0.56
33
40
50
56
diisopropylamide
(KDA)
and
N,N,N′,N′-
tetramethylethylenediamine (TMEDA) in continuous flow in a
hexane:tetrahydrofuran (THF) mixture.
Whereas KDA was usually prepared by the Schlosser method
by mixing LDA (lithium diisopropylamide) with tBuOK,[6] we have
envisioned to prepare this base in the absence of any lithium salts,
using a modified procedure of Collum for the preparation of
NaDA.[7] Thus, small slices of oil-free solid potassium suspended
in hexane were mixed with diisopropylamine. The resulting
suspension was cooled to 0 °C and isoprene was added dropwise.
After 30 min of stirring at 0 °C, the suspension was warmed to
25 °C leading after 6 h reaction time to a dark solution (Table 1,
0.57
(0.49)
57
5
DIPA
1.0
0.5
18
(49)[a]
6
7
8
DIPA
TMPH
HNCy2
3.0
1.0
1.0
1.5
0.5
0.5
18
6
0.33
0.20
0.28
99[b]
20
6
28
Yield of KDA/TMEDA in cyclohexane. [b] Potassium was used as limiting
[a]
reagent, DIPA was used in excess (3.0 equiv).
1
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In preliminary experiments, we have optimized the reaction
conditions for performing metalations with KDA/TMEDA in
hexane and in continuous flow using benzofuran (1a) in THF as
substrate and adamantanone (2a) as quenching reagent. We
have varied the temperature, the flow rate and the reactor size
(reactor volume) and have found that it was best to perform the
metalation at -78 °C using 1.5 equiv of KDA/TMEDA, a 4 mL tube
reactor and a combined flow rate of 10 mL/min leading to a
reaction time of 24 s for the metalation.[8] The resulting potassium
organometallic 3a was then quenched with adamantanone (2a,
1.5 equiv) at -40 °C for 10 min leading after work-up to the tertiary
alcohol 4aa in 95% isolated yield (Scheme 1).
Using Barbier-type conditions,[10] i.e. metalation of a mixture
of 1b (1.00 equiv) with 2a (1.50 equiv) with KDA/TMEDA (1.50
equiv) under the same flow conditions led to the alcohol 4ba in
74% yield (entry 1). Quenching of 3b with pivaldehyde (2c)
afforded the alcohol 5bc in 75% yield. Weinreb amides were
excellent acylation reagents for potassium organometallics and
the trapping of 3b with 2d and 2e gave the corresponding ketones
in 91-93% yield (entries 4-5). Thiolation of 3b with Bu2S2 (2f) led
to the thioether 4bf in 92% yield. The corresponding Barbier
reaction proceeded in this case with only 47% yield (entry 6).
We have extended the reaction scope to various heterocyclic
and aromatic substrates. For example, benzothiophene
derivatives 1c and 1d were metalated with KDA/TMEDA and
quenched with iodine (2g) or the aromatic aldehyde 2h as well as
the disulfide 2i leading to the expected products (4cg, 4dh and
4di) in 63-98% yield (Table 3, entries 1-3). A complete
regioselectivity of the metalation of 3-octylthiophene (1e) was
observed and addition to dicyclopropyl ketone (2j) gave the
tertiary alcohol 4ej in 65% yield (entry 4). Similarly, 2-
phenylthiophene 1f was metalated with KDA/TMEDA and trapped
with 2a affording 4fa in 80% yield (entry 5). 2-Methoxypyrazine
(1g) was regioselectively metalated at position
3
with
Scheme 1. Metalation of benzofuran (1a) with KDA/TMEDA and subsequent
[a]
KDA/TMEDA (-78 °C, 0.18 s using a combined flow rate of 10
mL/min). Addition of ketone 2a gave the desired alcohol 4ga in
81% yield (entry 6).
trapping with adamantanone (2a) in continuous flow.
Isolated yield of
analytically pure product. [b] Cyclohexane was used as solvent.
These potassium organometallics display a high reactivity and
the metalation of benzothiazole under optimum conditions[9] (flow
rate: 10 mL/min; reaction time: 0.18 s; reactor volume: 0.03 mL;
reaction temperature: -78 °C) furnished a potassium intermediate
3b, which was trapped with various electrophiles like ketones
(adamantanone (2a) or norcamphor (2b)) leading to the tertiary
alcohols 4ba and 4bb in 74–77% yield (Table 2, entries 1-2).
Table 3. Metalation of (hetero)arenes of type
continuous flow and subsequent batch quench with various electrophiles of type
2 leading to functionalized (hetero)arenes of type 4.
1 using KDA/TMEDA in
substrate of type 1
entry
1
T [°C], t [s],
electrophile of type 2[a]
product of type 4[b]
4cg: 63%[c]
flow rate [mL/min]
I2
Table 2. Metalation of benzothiazole (1b) using KDA/TMEDA in continuous flow
and subsequent batch quench with various electrophiles of type 2 leading to
functionalized benzothiazole derivatives of type 4.
1c: -78, 24, 10
1d: -78, 0.18, 10
2g
2
3
2h
2i
4dh: 98%
4di: 93%
1d: -78, 0.18, 10
entry electrophile
product
entry electrophile
product
of type 2
of type 4[a]
of type 2
of type 4[a]
4
5
6
7
1e: -78, 0.18, 10
1f: -78, 0.18, 10
1g: -78, 0.18, 10
1h: -78, 24, 10
2j
4ej: 65%
4fa: 80%
4ga: 81%
4ha: 42%
4ba: 77%,
2a
2a
2a
1
2a
4
2d
4bd: 91%
(74%)[b]
2
3
2b
Pivaldehyde
2c
4bb: 77%
4bc: 75%
5
6
2e
Bu2S2
2f
4be: 93%
4bf: 92%, (47%)[b]
[a] Yield of analytically pure isolated product. [b] Barbier-type reaction using a pre-
mixed solution of benzothiazole (1.00 equiv) and electrophile (1.50 equiv),
instant quench with NH4Cl.
8
1i: -78, 24, 10
2k
4ik: 82%
2
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Bu2S2
9
1i: -78, 24, 10
2f
4if: 73%
10
1j: -78, 0.18, 10
2h
4jh: 71%
[a]
[b]
1.50 equiv of electrophile were used.
Yield of analytically pure isolated
product. [c] KDA/TMEDA was prepared in cyclohexane. [d] Barbier-type reaction
using a pre-mixed solution of 1,3-dimethoxybenzene (1i, 28 mg, 0.20 mmol,
1.00 equiv) and adamantanone (2a, 45 mg, 0.30 mmol, 1.50 equiv), instant
quench with NH4Cl.
Scheme 3. Metalation of thioanisole (5a) using various lithium and potassium
bases under batch and flow conditions. [a] Yield of analytically pure isolated
product obtained in continuous flow. [b] Yield of analytically pure isolated product
obtained under batch conditions.
Extension to various aromatic substrates was possible.
Electron-poor trifluoromethylbenzene (1h) was metalated in
ortho-position with KDA/TMEDA (-78 °C, 24 s reaction time, 10
mL/min combined flow rate) providing after addition of 2a the
alcohol 4ha in 42% yield (entry 7). Electron-rich substrates such
as 1,3-dimethoxybenzene (1i) and 1,2,4-trimethoxybenzene (1j)
were metalated with KDA/TMEDA and gave after batch
quenching with aldehydes 2k and 2h and Bu2S2 (2f) the
corresponding adducts 4ik, 4if and 4jh in 71-82% yield (entries 8-
10).
Whereas lateral alkali-metalations of arenes were well
described in batch,[14] the corresponding reactions in flow were
rare.[15] The use of KDA/TMEDA was quite advantageous for the
metalation of methyl-substituted arenes (Table 4). Preliminary
results show, that a 0.2 M solution of toluene (9a) led to
unsatisfactory results, however the injection of neat toluene (9a)
improved considerably the flow metalation with KDA/TMEDA.
Interestingly, this metalation was performed at 25 °C (in contrast
to previously described metalations of arenes and heteroarenes).
In this case, the reaction time was increased to 24 s at a flow rate
of 10 mL/min. Under these convenient conditions, a subsequent
batch-trapping with ketone 2a gave 11aa in 69% yield. Similarly,
p-xylene (9b) provided the mono-potassium derivative 10b, which
after quenching with dodecyl iodide (2m) or Weinreb amide 2e
afforded the products 11bm and 11be in 95-96% yield. Mesitylene
(9c) was metalated neat and after quenching with ketone 2n and
dodecyl iodide (2m) gave the arenes 11cn and 11cm in 89-92%
yield. In the case of the Wurtz-type coupling with 2m, the reaction
was ten-fold scaled up to a 3 mmol scale,[16] providing 11cm in
93% yield. For 1-methylnaphthalene (9d), a 0.2 M solution in THF
was used and standard KDA/TMEDA-metalation led after
trapping with ketone 2a to the corresponding naphthylmethyl
alcohol 11da in 92% yield. Functionalized substrates such as 2-
fluorotoluene (9e) were metalated at the benzylic position,
affording the potassium organometallic 10e, which after
quenching with ketone 2j led to the tertiary alcohol 11ej in 66%
yield. N,N-diisopropyl-2-methylbenzamide (9f) led upon reaction
with KDA/TMEDA at -40 °C (reaction time: 24 s) solely to the
lateral metalated species 10f, completely avoiding ortho
metalation.[1d, 17] Trapping with various electrophiles such as
ketone 2j, alkyl iodide 2m and Weinreb amide 2o gave the
expected products 11fj, 11fm and 11fo in 75-93% yield. Further,
ketones were tolerated. For example, lateral metalation of ketone
9g using KDA/TMEDA proceeded smoothly at -40 °C within
0.18 s using a flow rate of 10 mL/min. Batch trapping with ketone
2j and cinnamyl bromide (2p) in the presence of 10% CuCN·2LiCl
resulted in the tertiary alcohol 11gj and the allylated ketone 11gp
in 72-90% yield. We further extended the substrate scope to
methyl-substituted heterocycles such as 2-chloro-3-methyl-
pyridine (9h). Metalation of 9h at the meta-methyl substituent
using KDA/TMEDA led to the corresponding organopotassium
species 10h, which after batch quench with various carbonyl
Scheme 2. Metalation of 3-methoxy benzonitrile (1k) with KDA/TMEDA in
continuous flow and subsequent trapping with various electrophiles. [a] Yield of
[b]
analytically pure isolated product Yield of analytically pure isolated product
obtained under batch conditions.
Remarkably, aromatic nitriles were tolerated in such
metalations and 3-methoxybenzonitrile (1k) was deprotonated at
position 2 by KDA/TMEDA (-78 °C, reaction time: 0.18 s). The
resulting arylpotassium derivative 3k reacted with various
electrophiles (ketone 2j, pivaldehyde (2c) and TMS-Cl (2l))
leading to the expected products 4kj, 4kc and 4kl in 62-88% yield.
Performing the metalation of 1k with KDA/TMEDA in batch
followed by Me3SiCl quenching afforded the product 4kl in 78%
yield. A Wurtz-type coupling[11] using primary alkyl iodides such
as dodecyl iodide (2m) led to the alkylated 3-methoxybenzonitrile
4km in 53% yield. (Scheme 2). Then, we turned our attention to
substrates being able to undergo lateral metalation. Thus,
thioanisole (5a) was previously lithiated with BuLi and DABCO or
HMPA leading to PhSCH2Li (6a).[12] However, LDA did not
achieve a lithiation neither in batch nor in flow.[13] On the other
hand, KDA/TMEDA successfully deprotonated 5a in batch as well
as in flow (Scheme 3) affording PhSCH2K (7a), which was
quenched with ketones 2a and 2j and alkyl iodide 2m resulting in
the desired products 8aa, 8aj and 8am in 62-99% yield.
3
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electrophiles (2a, 2q, 2n and 2r) gave the corresponding alcohols
11ha, 11hq, 11hn and 11hr in 75-97% yield.
instantly with various electrophiles affording functionalized
(hetero)arenes in high yields. This flow procedure was
successfully extended to the lateral metalation of methyl-
substituted arenes and heteroaromatics resulting in benzylic
potassium organometallics, which were trapped with a range of
electrophiles. A scale-up was possible without further optimization.
Further investigations of flow metalations using KDA/TMEDA are
currently under way in our laboratories.
Table 4. Lateral metalation of methyl-substituted (hetero)arenes using
KDA/TMEDA in continuous flow leading to organopotassium species of type 10.
Subsequent batch trapping with various electrophiles afforded functionalized
methyl-substituted (hetero)arenes of type 11.
Acknowledgements
N. Weidmann thanks the German Academic Scholarship
Foundation for a fellowship. We thank the DFG and LMU for
financial support. We further thank BASF (Ludwigshafen) and
Albemarle (Frankfurt) for the generous gift of chemicals and
Uniqsis for technical support.
Keywords: flow chemistry • lateral metalation • potassium•
arene • heteroarene
[1]
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[2]
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Yields of analytically pure isolated products [a] substrate (neat), E-X (0.30 mmol,
1.00 equiv), KDA/TMEDA (1.10 equiv), 25 °C, 24 s, 10 mL/min. [b] Wurtz-type
[c]
coupling from the corresponding iodide.
from the corresponding Weinreb
amide. [d] Scale-up to 2.0 mmol using the optimized flow conditions. [e] 25 °C, 24
s, 10 mL/min [f] -40 °C, 24 s, 10 mL/min. [g] 40 °C, 0.18 s, 10 mL/min. [h] 10 mol%
CuCN·2LiCl. [i] -78 °C, 0.18, 10 mL/min.
Trapping 10h with alkyl iodide 2m and cinnamyl bromide 2p
(in the presence of 10% CuCN·2LiCl) led to the corresponding
products 11hm and 11hs in 66-77% yield. Pyrazine 9i was
metalated in continuous flow with KDA/TMEDA. We have found
that after metalation at the methyl-substituent the heterobenzylic
potassium organometallic 10i was obtained. Batch trapping with
dibutyl disulfide (2f) and dodecyl iodide (2m) gave the
functionalized pyrazines 11if and 11im in 79-95% isolated yield.
[5]
[6]
a) N. Weidmann, M. Ketels, P. Knochel, Angew. Chem. Int. Ed. 2018, 57,
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Organomet. Chem. 1998, 558, 193; b) L. Lochmann, J. Trekoval, J.
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Lochmann, M. Janata, Cent. Eur. J. Chem. 2014, 12, 537; f) for
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R. E. Mulvey, S. D. Robertson, J. G. Alvarez, Angew. Chem. Int. Ed.
2010, 49, 318; Angew. Chem. 2010, 122, 3250.
In summary, we have reported a preparation of the potassium
base KDA/TMEDA in the absence of any lithium salts and have
demonstrated its utility for the metalation of (hetero)arenes
containing sensitive functional groups using a flow set-up. The
resulting potassium organometallics react upon batch quench
[7]
Y. Ma, R. F. Algera, D. B. Collum, J. Org. Chem. 2016, 81, 11312.
4
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COMMUNICATION
[8]
Commercially available equipment from Uniqsis was used. For a detailed
optimization, see SI, page 8-9.
[9]
Optimization studies of the flow conditions were separately conducted for
each substrate.
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Semmelhack, J. W. Herndon, Organometallics, 1983, 2, 363; c) The use
of TMEDA and 2.2 equiv of nBuLi leads to dimetalation of thioanisole; S.
Cabiddu, C. Floris, S. Melis, Tetrahedron Lett. 1986, 27, 4625.
[13] For detailed screening conditions, see SI, page 6-7.
[14] a) P. Fleming, D. F. O´Shea, J. Am. Chem. Soc. 2011, 133, 1698; b) A.
Manvar, P. Fleming, D. F. O´Shea, J. Org. Chem. 2015, 80, 8727; c) F.
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10.1002/anie.202003392
Angewandte Chemie International Edition
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Potassium in Flow: A metalation of functionalized (hetero)arenes with KDA (potassium diisopropylamide)/TMEDA was performed
using a commercial continuous flow set-up leading to the corresponding potassium organometallics. Trapping with various
electrophiles gave polyfunctionalized (hetero)aromatics in good yields. Further, the flow procedure was extended to the lateral
metalation of methyl-substituted (hetero)arenes resulting in benzylic potassium organometallics, which were trapped with various
electrophiles.
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